Currently total hip and knee joint replacements (arthroplasty) are the most common major orthopedic surgical procedures, with approximately 1 million performed world-wide annually. A major proportion of these prostheses are anchored to the contiguous cancellous bone in an acrylic based bone cement, which serves to immobilize the implant and distribute force from it to the adjoining bone. (see, Lewis, G., J. Biomed. Mater. Res. B. Appl. Biomater., 38:155-182 (1997); Lewis, G., J. Biomed. Mater. Res. B. Appl. Biomater., 84:301-319 (2007); Lewis, G., J. Biomed. Mater. Res. B. Appl. Biomater., 89:558-574 (2009)).
Despite strict antiseptic operative procedure deployed against infection, postoperative osteomyelitis remains a considerable problem in orthopedic surgery. The infection rates of joint replacement range from 1-3% after surgery operation. For infected cases, total removal of the implant is often necessary and usually leads to severe functional disability. Such infections are very costly in terms of quality of life and public health expenditure. In order to reduce the risk of post-operative infection, it is of great interest to release antibiotics at the implanted local site (see FIG. 1). The main goals of the drug releasing systems are to maintain drug levels at the desired therapeutic range with just a single dose and to localize delivery of the drug to a specific body compartment, thereby reducing the need for follow-up care and increasing patient comfort and/or compliance.
There are over 30 commercially available basic acrylic bone cements for use in cemented arthoplasties. Some of the most widely used brands are Simplex P (Styker Co.), Palacos R (Heraeus Kulzer), SmartSet HV (DePuy Co.) and Vertefix Radiopaque (Cook Medical). In general, all brands contain polymer powder and liquid monomer components that are mixed together to form a dough-like bone cement. The polymer powder consists of prepolymerized poly(methyl methacrylate) (“PMMA”) beads or a PMMA-based polymer; benzoyl peroxide as the initiator of the polymerization reaction; and a radiopacifier of barium sulfate or zirconium dioxide. The liquid monomer comprises of methyl methacrylate monomer; N,N-dimethyl-p-toludine (DMPT) as the accelerator of the polymerization reaction; and hydroquinone as an inhibitor of that reaction.
To date, the commercially available antibiotic delivery systems (e.g., SmartSet GHV (DePuy Co.); Simplex P with Tobramycin (Stryker)) are based on antibiotic loaded poly(methyl methacrylate) (PMMA) bone cement. The main problem of the current composite bone cements is their inability to maintain sustained drug release for several weeks at the site of implantation. These drug delivery systems are based on the method of loading the drug agents into the polymer and/or monomer components of the cement by mechanical mixing or by adsorption directly into the matrices of polymer (see Padilla et al. J. Controlled Release, 83:343-52 (2002); Anagnostakos, K. and Kelm J., J. Biomed. Mater. Res. B. Appl. Biomater., 90B:467-475-182 (2009)). However, such techniques do not achieve sustained drug release at the implanted site for more than a few days. At initial stages following surgery, the typical bone cements elute antibiotics located at the surface of the interface between the cement and the adjacent tissue or medium, and not the sub-layers of the bone cement. The diffusion of drug becomes more limited in the later stages. As more than 90% of the antibiotic may be retained within the PMMA matrix, the bone cement cannot function to protect the surrounding tissue from infection.
Recent advancements in the design and development of mesoporous nanomaterials have highlighted their potential for drug delivery. These nanomaterials are characterized by high relative surface areas, tunable pore volumes, controllable surface functionalities, and well-ordered pore structures. FIG. 2 depicts a microscopy image of the organized structure of mesoporous nanorods. Examples of mesoporous nanomaterials include mesoporous silica nanoparticles, alumina nanofibers, carbon nanotubes, titania nanotubes, hydroxyapatite nanorods, and hydroxyapatite nanoparticles. Mesoporous silica nanoparticles (MSN) have large specific pore volumes (e.g., range from 0.6-1 cm3/g) and high surface areas (e.g., range of 700-1000 m2/g), making it possible to load the nanoparticles with drug and reach loading levels that exceed 30 wt % (see, Gao et al., J. Phys. Chem. B., 113:1796-804 (2009); Vellet-Regi et al., J. Intern Med., 267:22-43 (2009); Rosenholm et al., Nanoscale, 2:1870-83 (2010)).
In view of the foregoing developments, there is a need to develop bone cements with improved sustain release of antibiotics. The present invention satisfies this and other needs.